The overall goal of this proposal is to understand the transcript degradation pathway and its relationship to translational control, using the budding yeast S. cerevisiae as a model system. The focus is on the XRN1 gene, encoding the major 5'-3' exoribonuclease activity of yeast and believed to be the major catabolic enzyme in the late stages of the RNA turnover pathway. The investigator intends to identify other genes in the pathway by screening for mutations that are synthetically lethal with xrn alleles (Aim 1) and to characterize the mutants obtained (including the already known SKI2 gene) in RNA turnover and translation, in vivo (Aim 2) and in vitro (Aim 4). Aim 3 is directed at targeted mutagenesis of XRN1 to analyze its functional domains and obtain dominant negative mutations. Many proteins involved in RNA turnover and translation control appear highly conserved among eukaryotes and are thought to help the cell respond to such challenges as pathogenic infection and oncogenesis.